The presence of uric acid is implicated in several human disorders, including gout. Gout is a metabolic disease marked by a painful inflammation of the joints, deposits of urates in and around the joints, and usually an excessive amount of uric acid in the blood. Gout is generally treated in one of four ways:
(1) uricosuric agents to increase renal function (enhanced fluid elimination); PA1 (2) colchicine, a microtubule inhibitor; PA1 (3) non-steroidal anti-inflammatory agents, e.g., indomethacin; and PA1 (4) allopurinol, a xanthine oxidase inhibitor. PA1 R.sub.5 is hydrogen or ZH;
5-pyrimidinecarboxamides, and particularly 5-carboxamides of barbituric acid, have previously been described as useful for various therapeutic purposes. For example, Takeda Pharmaceutical Industries' Japanese Patent Publication No. 1,445/64, published on Feb. 14, 1964, suggests the use of compounds of the formula: ##STR3## i.e., 5-phenylcarbamoylbarbituric acid (wherein R is hydrogen) and 1-substituted-phenylcarbamoylbarbituric acids (wherein R is alkyl or phenyl), as potential anti-cancer agents.
Analogs of similar barbituric acid derivatives have also been described in the literature. Thus, N-substituted-2-amidocarbonylthiobarbituric acids of the formula: ##STR4## wherein R.sub.1 is alkyl, alkenyl, various substituted alkyl, alkenyl or carbonyl, or optionally substituted aryl or aralkyl; R.sub.2 and R.sub.3 are each independently alkyl, alkenyl, cycloalkyl, aryl, aralkyl or hydrogen, provided that not more than one of R.sub.2 and R.sub.3 is hydrogen; and X is oxygen or sulfur, are disclosed in Bayer AG German Offen. No. 24 05 732 and in Kramer et al., U.S. Pat. No. 3,961,061 granted on June 1, 1976. These thiobarbituric acid derivatives are described as possessing insecticidal, acaricidal, fungicidal and bactericidal properties.
Other 5-carboxamido-substituted thiobarbituric acids such as: ##STR5## wherein X is oxygen or sulfur; R.sub.1 and R.sub.2 may each by alkyl, alkenyl, benzyl or unsubstituted or substituted phenyl; R.sub.3 may be halogen, nitro or trihalomethyl; R.sub.4 is hydrogen, halogen or trihalomethyl; and R.sub.5 is hydrogen, halogen, methyl or methoxy, are also described in he patent literature. Such compounds are disclosed in Ciba-Geigy European Patent Publication No. 74,335 and in DeSousa et al., U.S. Pat. No. 4,283,444 granted on Aug. 11, 1981, as useful for protecting keratinous materials, especially wool, from insect attack.
More recently, it has been disclosed in Brewer et al. U.S. Pat. No. 4,634,707, owned by the assignee of the present invention, that certain 5-carboxamide-2-thiobarbituric acid derivatives, viz., compounds of the formula: ##STR6## wherein R is hydrogen, 2 or 3-halo, 2-methyl, 4-fluoro, 4-(C.sub.1 -C.sub.6 alkoxyl), 2 or 4-trifluoromethyl, or hydroxyl, and R.sub.1 is hydrogen; or R is 2-fluoro and R.sub.1 is 4-fluoro; or R is 2-methoxy and R.sub.1 is 5-methyl; and R.sub.2 and R.sub.3 are hydrogen atoms or carbohydrate residues, and the pharmacologically acceptable addition salts thereof, induce regression or inhibit the growth of leukemia and various malignant tumors in mammals.
The use of yet other 5-pyrimidinecarboxamides as anti-leukemia and anti-tumor drugs is disclosed in Brewer et al. U.S. Pat. No. 4,636,508, also owned by the present assignees.
It is among the objects of the present invention to provide a therapeutic method for reducing serum uric acid levels in man or other mammals, utilizing the preceding and other 5-pyrimidinecarboxamide derivatives. Other objects and advantages of the invention will be apparent from the following detailed description of preferred embodiments thereof.